Our investigative team has recently discovered a genetic association between late-onset Alzheimer's disease and the apolipoprotein E (APOE, gene; apoE, protein) epsilon-4 gene. This finding has triggered many recent studies showing an important role of apoE in the determination of neurologic injury and recovery following a variety of acute ischemic insults including intracerebral hemorrhage, closed head injury, acute stroke and dementia pugilistica (chronic traumatic brain injury). An important aspect of our work is the finding of an association between APOE4 and neurocognitive decline after cardiac surgery. Although mounting evidence suggests apoE plays a role in acute and chronic neurological disease, the mechanism underlying these observations and the influence of aging is not completely understood. We hypothesize that a genetic predisposition exists for the easily documented neurologic and neurocognitive dysfunction observed after anesthesia and surgery. ApoE may play a role in modulating the inflammatory response to ischemia and perioperative stress. We have recently determined that ApoE, in vivo, modulates the release of nitric oxide and TNF-alpha in glial cells. This may compound the autonomic dysregulation that we recently reported in the elderly. The combination of these two factors may modulate an exaggerated inflammatory response increasing the susceptibility to perioperative injury. Our pilot data associating APOE4 with cognitive impairment after cardiac surgery support this hypothesis. Therefore, we propose to determine the association between post-operative neurocognitive dysfunction, neurocognitive recovery, and APOE4 genotype in patients undergoing thoracic and vascular surgery. The unifying hypothesis is that a genetic susceptibility to neurologic dysfunction after surgery results either from a predisposition to immunologic dysregulation, the failure of normal genetically encoded reparative processes, or a combination of these mechanisms resulting in a greater incidence and severity of neurocognitive dysfunction and reduction in quality of life and independence in the aging population after surgery. Thus, our extensive preliminary work as well as our expanded collaborative interdisciplinary research group including cardiac anesthesiologists, cardiac surgeons, neuroscientists, geneticists and neurologists is uniquely able to investigate the genetic predisposition to neurocognitive dysfunction after surgery. Such an association is an important first step in elucidating the mechanism underlying genetic susceptibility to ischemic insults, and designing interventional strategies to improve outcome.